1. Field of the Invention
The invention herein relates to the field of chemical processes for the preparation of 2-haloacetamides, particularly those having as one nitrogen substituent an alkyl, alkenyl, alkynyl, alkoxyalkyl or heterocycyl group and, additionally, an alkenyl or cycloalkenyl radical or a phenyl group substituted with various radicals.
2. Description of the Prior Art
2-haloacetamides of the types described herein have been prepared by a variety of means known to the prior art. In one prior art process, described in U.S. Pat. No. 2,863,752 (Re 26,961) N-substituted-2-haloacetanilides are prepared by reacting a primary or secondary amine with the acid chloride of haloacetic acid typically in the presence of caustic soda to neutralize the by-product hydrogen halide. A similar process is described in German OLS No. 1,903,198 and U.S. Pat. Nos. 3,937,730 and 3,952,056 wherein the intermediates and final products are characterized by the N-substituent lower alkoxyethyl wherein the ethyl radical may have one or two methyl groups attached thereto.
In yet another prior art process described in U.S. Pat. No. 3,574,746, N-substituted-N-cycloalkenyl-2-haloacetamides are prepared by the haloacetylation of the corresponding N-substituted-cycloalkylidene amine in the presence of an acid acceptor.
In U.S. Pat. Nos. 3,630,716 and 3,637,847 a process is described for producing a-haloacetanilides which comprises reacting an aromatic amine with formaldehyde to produce the corresponding N-methylene amine (or azomethine) which is then reacted with a haloacetylating agent to produce the corresponding N-(halomethyl)-substituted 2-haloacetanilide. The latter product itself has herbicidal properties, but can further be reacted with an alcohol to produce the corresponding herbicidal N-(alkoxymethyl)-2-haloacetanilides as described in U.S. Pat. Nos. 3,442,945 and 3,547,620. In an analogous manner, the above process is described as useful for producing aliphatic 2-haloacetamides in U.S. Pat. No. 3,287,106.
Another process of the prior art for producing 2-haloacetamides involves the reaction of an appropriate aldehyde or ketone with an appropriate primary amine to produce the corresponding Schiff base which is then reacted with a haloacetic acid halide with the elimination of hydrogen chloride. See South African Pat. No. 753,918 and J. P. Chupp et al J.O.C. 33, 2357 (1968).
Still another process of the prior art for producing secondary 2-halo-N-(1-alken-1-yl) acetamides is to react chloracetamide with the appropriate aldehyde under conditions that eliminate water. See, e.g., German Pat. No. 2,155,494.
U.S. Pat. Nos. 4,025,648, 4,046,911 and 4,032,657 describe processes for producing fungicidal acetanilides or 2-haloacetanilides by acylating ('911 patent) or haloacylating the corresponding N-alkylated aniline.
The process of the present invention involves successfully alkylating primary or secondary 2halo amides under anion-forming conditions to produce useful tertiary 2-haloacetamides. That this process is totally novel and unexpected is made apparent by consideration of numerous criteria discussed below. In the discussion below the terms "alkylation" or "alkylating" are used generically to include reactions which give rise to various substituents (not just alkyl groups) on the primary or secondary amide anion.
Alkylation of amides via the anion is well known in the prior art, but care is taken to avoid substrates containing labile moieties which would interfere with the reaction. Furthermore, in alkylation of amidic-type materials, by-product imidate sometimes forms, arising from oxygen alkylation rather than nitrogen alkylation of the secondary amide (see for instance, J. R. Pougny et al, Organic Preparations and Procedures Int. 9, 5-8 (1977)). This side reaction has the effect of unpredictably reducing yields of the desired tertiary amide.
As illustrative of prior art amide alkylations, one process is described in the prior art wherein N-1-cyclohexen-1-yl) acetamide is reacted with sodium hydride at room temperature, with N-alkylation by methyl iodide, to give the N-methyl-N-cyclohexen-1-yl acetamide in good yield. R. B. Boar et al, J.C.S. Perkin I. 1237 (1975). In like manner, other investigators demonstrated that formamide and secondary formamide could be successfully N-alkylated with chloromethyl methyl ether via amide anion generation with sodium hydride (V. Schollkopf et al, "Angew. Chem." (English Ed.) 15 (1976); German Ed. 88, 296 (1976). G. L. Isele et al (Synthesis, pages 266-68 (1971) describe amide N-alkylation with hydrocarbyl halides in KOH/dimethylsulfoxide media. Similarly, Brehme disclosed the alkylation of acylanilines with methyl iodide under basic conditions in the presence of a phase transfer catalyst to produce the corresponding N-methylated acetanilide. See Synthesis, 113-114 (1976).
In the above-mentioned U.S. 4,032,657 patent, reference is made to an amide anion alkylation process wherein the acyl moiety of the secondary amide was deemed to be inert under conditions of the reaction.
It is not known in the prior art to alkylate anions of primary and secondary 2-haloacetamides to produce tertiary 2-haloacetamides, i.e., the process of the present invention. These 2-haloacetamide compounds have highly effective biological properties, e.g., as herbicides and plant growth regulators and safeners or as fungicides.
When prior workers have formed the anion of secondary or tertiary 2-haloacetamides, a variety of products have resulted, arising from elimination of the single alpha-halogen which is well known for its lability and facile displacement in 2-haloacetamides under a variety of conditions, including those of anion formation. For example, the low temperature treatment of certain secondary 2-haloacetamides with potassium, KOH or potassium t-butoxide as strong bases resulted in facile loss of halogen and the formation of diketopiperazines, .alpha.-lactams (aziridinones) or ring-opened products of the latter. See exemplary work by J. C. Sheenan et al as reported in articles in J.A.C.S. 83, 4792 (1961); ibid 86, 746 and 1356 (1964); ibid 89, 362, 366 (1967); ibid 91, 1176, 4596 (1969); ibid 95, 3415 (1973) and in J.O.C. 31 4244 (1966); ibid 35, 4246 (1970); by S. Sarel in J.A.C.S. 82, 4752 (1960) and in J.O.C. 23, 330 (1958) and by Baumgarten et al in J.A.C.S. 83, 4469 (1961); ibid 85, 3303 (1963) and by Baumgarten in J.A.C.S. 84, 4975 (1962); M. Kakimoto et al, Chemistry Letters, 47-48, 1976. N-alkylations via Michael-type additions to activated olefins are also known. See B. C. Challis et al, The Chemistry of Amides, pages 748-753 (1970); The Chemistry of Functional Groups, Ed. J. Zabicky, Interscience (Publisher).
Tertiary 2-haloacetamides are known to be not particularly stable to strong base under anion forming conditions; by themselves they can be easily transformed, with loss of .alpha.-halogen, to carbenoid intermediates and thence to olefins, and/or cyclopropane derivatives and the like or, in the presence of alkylating agents such as aldehydes and ketones, halogen is lost with formation of glycidic amides or degradation products therefrom. See, e.g., A. J. Speziale et al, J.O.C. 30, 1199 (1965); ibid 26, 3176 (1961) and B. G. Chatterjee et al, J.O.C. 30, 4101 (1965).
Therefore, the prior art relevant to amide alkylations exemplified above teaches that on treatment of 2-haloacetamides under anion-forming conditions, alpha-halogen is eliminated or indeed the alpha-methylene moiety destroyed, giving rise to entirely different products than those predicted on simple N-alkylation described below.
The prior art processes described above have certain inherent limitations and disadvantages. For example, the azomethine process referred to above in U.S. Pat. Nos. 3,630,716 and 3,637,847 is generally restricted to the use of basic or electron-rich primary anilines as starting materials. As electron withdrawing groups are increasingly substituted onto the aryl ring, condensation of the aniline with formaldehyde to form azomethine or the latter with haloacetyl halide becomes increasingly inhibited and finally largely inoperative. Thus the azomethine process gives poor or completely unsuccessful results in the production of herbicidally useful N-(alkoxymethyl) 2-haloacetanilide variously substituted, particularly in the ortho position, with alkoxy, halogen, nitro, trifluoromethyl and other electron-withdrawing groups.
Yet another limitation on the azomethine process is the inability to produce N-(1-alkoxy-1-ethyl) or N-(1-alkoxy-1-propyl)-2-haloacetanilides from the corresponding N-ethylidene or N-propylidene anilines. When these Schiff bases are reacted with an acetylating agent, e.g., chloroacetyl chloride, the resulting adducts are not stable and unlike similar adducts from the azomethines and chloroacetyl chloride, cannot be successfully reacted with alcohols to give desired N-(alkoxyalkyl) substitution. Rather, hydrogen chloride is eliminated to form N-alkenyl-2-haloacetanilides.
Yet another limitation identified in the prior art is the inability to produce N-(alkoxymethyl)-N-(1-cyclohexen-1-yl)-2-haloacetamides. Thus, 1-cyclohexen-1-yl amines are generally unknown and therefore unavailable for reaction with formaldehyde to form the requisite N-(1-cyclohexen-1-yl) azomethine. Moreover, the known tautomers, i.e., ring substituted N-(cyclohexylidene) amines are strongly resistant to azomethine formation. Furthermore, although N-substituted N-(cyclohexylidene) amines (i.e., imines), are known and provide the necessary starting materials for N-(substituted)-N-(1-cyclohexen-1-yl) 2-haloacetamides (U.S. Pat. No. 3,574,746), imine formation is conditioned on the availability of ketone and primary amine. This availability is completely lacking in the case of primary alkoxymethyl amines owing to their inherent instability and non-existence. Thus, N-(alkoxymethyl)-N-(1-cyclohexen-1-yl)-2-haloacetamides are also unavailable by the aforementioned ketimine route. The above considerations also apply to the acyclic N-(1-alken-1-yl)-2-haloacetamides, such that those materials likewise are incapable of materializing by known routes.
It is apparent from the above that in the aforementioned U.S. Pat. No. 3,574,746 and South African Patent No. 753,918, the disclosed processes can be used to produce only 2-haloacetamides having no less than two carbon atoms between the nitrogen and oxygen atoms of the N-(alkoxyalkyl) moiety.
One further limitation noted in prior art processes was the difficult, if not impossible, reaction of certain substituted phenyl-N-(halomethyl)-2-haloacetanilides with methyl mercaptan or salts. Thus, attempts to prepare thio-alachlor, i.e., 2',6'-diethyl-N-(methylthiomethyl)-2-chloroacetanilide, by the reaction of methyl mercaptan or its salt with the corresponding N-chloromethyl intermediates were unsuccessful.
It is therefore a primary object of this invention to provide a novel process for preparing in situ anions of secondary 2-haloacetamides as intermediate species which when reacted with other starting materials from hindered or unhindered tertiary 2-haloacetamides, which process suffers none of the above-mentioned disadvantages.
It is a further object of this invention to provide a simple and economic process for the production of 2-haloacetamides which can be substituted on the amide nitrogen with aliphatic, cycloaliphatic and/or aromatic substituents in high yield and assay.
Still another object of this invention is the provision of a process which can produce for the first time 2-haloacetamides which can be substituted on the amide nitrogen atom simultaneously with alkoxymethyl and cycloalkenyl (e.g., 1-cycloalken-1-yl) radicals.
These are other objects will become apparent from the detailed description below.